Neuroactive drugs show promising effects against glioblastomas in preclinical studies

Researchers have found that the antidepressant vortioxetine could offer new hope to glioblastoma patients by crossing the blood-brain barrier and significantly reducing tumor size in preclinical models.

Study: High-throughput identification of reusable neuroactive drugs with potent anti-glioblastoma activity. Photo credit: Elif Bayraktar / Shutterstock.com

A recent Natural medicine The study investigates the potential to convert currently approved drugs for the treatment of cancer and neurological diseases to their therapeutic effect against glioblastomas.

Current treatment strategies for glioblastoma

Glioblastoma is an incurable and fatal form of brain tumor. About 50% of patients die within twelve months of diagnosis. The life expectancy of glioblastoma patients can be extended through radiation, chemotherapy or surgery.

Many drugs used to treat cancer cannot cross the blood-brain barrier, which limits their effectiveness in treating brain tumors such as glioblastoma. Targeted therapies have limited success in treating glioblastoma due to the lack of clinically predictive patient model systems and the presence of treatment-resistant glioblastoma stem cells (GSCs).

Recent studies on the pathophysiology of glioblastoma have reported synaptic integration of cancer cells into neuronal circuits, stem cell signatures that resemble neuronal development, and modulation of specific neurotransmitter pathways in the tumor microenvironment (TME). These features may reflect vulnerabilities of glioblastoma cells that may be therapeutically relevant, particularly when investigating the potential repurposing of existing “neuroactive” drugs (NADs).

The lack of effective treatments for glioblastoma underscores the importance of identifying neurotherapeutic vulnerabilities that can guide future drug discovery in this area. To date, the anticancer effects of most NADs have not been studied for the treatment of glioblastoma.

About the study

Pharmacoscopy is an ex vivo image-based drug testing approach that has been validated in functional precision studies to assess the effect of new drugs in the treatment of hematological malignancies. In the current study, the researchers used pharmacoscopy to simultaneously in vitro And in vivo Efficacy of both neuroactive and oncology drug libraries (ONCD) against samples from glioblastoma patients.

The neuroactive drug library consisted of drugs that can cross the blood-brain barrier and are currently approved to treat neurological diseases such as Alzheimer's disease, depression and schizophrenia. The ONCD drug library, on the other hand, consisted of conventional cancer treatments such as cyclin-dependent kinase (CDK) and receptor tyrosine kinase (RTK) inhibitors.

A total of 130 different active substances were used to treat tumor tissue from 27 patients who had recently undergone surgery at the University Hospital of Zurich. Imaging techniques and computer analyses were used to identify drugs that had an effect on the cancer cells.

Study results

Several ONCDs were able to penetrate the BBB, including elesclomol, osimertinib, and regorafenib.

Certain patient characteristics increased the sensitivity of their tumor cells to certain ONCDs. For example, age was associated with higher sensitivity to elesclomol, tumor samples from patients with TP53 mutations were more sensitive to the CDK4/6 inhibitor abemaciclib, and patients with loss of rearranged copies during transfection (RET) were more sensitive to pazopanib.

Fifteen NADs showed anti-glioblastoma activity, with the antidepressant vortioxetine showing significant ex vivo Efficacy in approximately 67% of patient samples. Other effective NADs were paroxetine, fluoxetine, and brexpiprazole.

Higher sertindole sensitivity was observed in patients with a loss of copy number of fibroblast growth factor receptor 2 (FGFR2). In addition, ex vivo Sensitivity to brexpiprazole has been observed in male patients.

A machine learning approach was developed to search for convergence of secondary drug targets analyzed by regulated regression (COSTAR). This model tested over a million compounds for their efficacy against glioblastoma and documented neuroactive convergence in activating protein 1 (AP-1)/BTG-driven suppression of glioblastoma. The shared signaling cascade of cancer and nerve cells is important and key to elucidating the selective therapeutic efficacy of certain NADs.

Vortioxetine was consistently the most effective NAD in vivoparticularly in combination with current standard treatment. Furthermore, the survival benefits associated with vortioxetine treatment were significant and similar to those of the alkylating agent temozolomide (TMZ).

Magnetic resonance imaging (MRI) scans of transplanted mice showed a significant reduction in tumor size after treatment with vortioxetine. In vitroVortioxetine reduced glioblastoma growth, clonogenic survival and invasiveness.

Consistent with previously reported results, paliperidone and citalopram were not associated with a survival benefit. The inefficacy of citalopram suggests that efficacy against glioblastoma is not achieved by serotonin modulation alone.

Conclusions

Various NADs, especially the antidepressant vortioxetine, caused rapid death of glioblastoma cells.

Although the study results are promising, vortioxetine should not be used to treat glioblastoma without appropriate medical supervision, as its effectiveness has only been demonstrated in vitro and in mice. Therefore, further clinical studies are needed to evaluate the therapeutic efficacy of vortioxetine in human glioblastoma patients.